11-57598250-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000062.3(SERPING1):c.-21T>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,544,846 control chromosomes in the GnomAD database, including 1,559 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 93 hom., cov: 31)

Exomes 𝑓: 0.043 ( 1466 hom. )

Consequence

SERPING1
NM_000062.3 splice_region

Scores

Splicing: ADA: 0.0005334

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.247

Publications

18 publications found

Variant links:

Genes affected

SERPING1 (HGNC:1228): (serpin family G member 1) This gene encodes a highly glycosylated plasma protein involved in the regulation of the complement cascade. Its encoded protein, C1 inhibitor, inhibits activated C1r and C1s of the first complement component and thus regulates complement activation. It is synthesized in the liver, and its deficiency is associated with hereditary angioneurotic oedema (HANE). Alternative splicing results in multiple transcript variants encoding the same isoform. [provided by RefSeq, May 2020]

SERPING1 Gene-Disease associations (from GenCC):

hereditary angioedema with C1Inh deficiency
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
C1 inhibitor deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary angioedema type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary angioedema type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SERPING1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015582442).

BP6

Variant 11-57598250-T-C is Benign according to our data. Variant chr11-57598250-T-C is described in ClinVar as Benign. ClinVar VariationId is 305015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0314 (4774/152100) while in subpopulation NFE AF = 0.0484 (3288/67970). AF 95% confidence interval is 0.047. There are 93 homozygotes in GnomAd4. There are 2260 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 4774 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SERPING1	NM_000062.3 link	c.-21T>C	splice_region_variant	Exon 2 of 8	ENST00000278407.9	NP_000053.2	P05155-1E9KL26
SERPING1	NM_000062.3 link	c.-21T>C	5_prime_UTR_variant	Exon 2 of 8	ENST00000278407.9	NP_000053.2	P05155-1E9KL26
SERPING1	NM_001032295.2 link	c.-21T>C	5_prime_UTR_variant	Exon 1 of 7		NP_001027466.1	P05155-1E9KL26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9 link	c.-21T>C		splice_region_variant	Exon 2 of 8	1	NM_000062.3	ENSP00000278407.4		P05155-1
SERPING1	ENST00000278407.9 link	c.-21T>C		5_prime_UTR_variant	Exon 2 of 8	1	NM_000062.3	ENSP00000278407.4		P05155-1

Frequencies

GnomAD3 genomes

AF:

0.0314

AC:

4776

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00834

Gnomad AMI

AF:

0.0771

Gnomad AMR

AF:

0.0226

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.000583

Gnomad SAS

AF:

0.00766

Gnomad FIN

AF:

0.0510

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0484

Gnomad OTH

AF:

0.0297

GnomAD2 exomes

AF:

0.0291

AC:

4285

AN:

147346

AF XY:

0.0292

show subpopulations

Gnomad AFR exome

AF:

0.00763

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.0000921

Gnomad FIN exome

AF:

0.0498

Gnomad NFE exome

AF:

0.0467

Gnomad OTH exome

AF:

0.0311

GnomAD4 exome

AF:

0.0429

AC:

59761

AN:

1392746

Hom.:

1466

Cov.:

AF XY:

0.0419

AC XY:

28767

AN XY:

686004

show subpopulations

African (AFR)

AF:

0.00745

AC:

235

AN:

31540

American (AMR)

AF:

0.0176

AC:

629

AN:

35638

Ashkenazi Jewish (ASJ)

AF:

0.0208

AC:

520

AN:

25046

East Asian (EAS)

AF:

0.0000559

AC:

AN:

35768

South Asian (SAS)

AF:

0.0105

AC:

829

AN:

79036

European-Finnish (FIN)

AF:

0.0537

AC:

2612

AN:

48670

Middle Eastern (MID)

AF:

0.0329

AC:

152

AN:

4626

European-Non Finnish (NFE)

AF:

0.0491

AC:

52764

AN:

1074900

Other (OTH)

AF:

0.0351

AC:

2018

AN:

57522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2586

5172

7758

10344

12930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1940

3880

5820

7760

9700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0314

AC:

4774

AN:

152100

Hom.:

Cov.:

AF XY:

0.0304

AC XY:

2260

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00831

AC:

345

AN:

41500

American (AMR)

AF:

0.0225

AC:

344

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3472

East Asian (EAS)

AF:

0.000584

AC:

AN:

5138

South Asian (SAS)

AF:

0.00766

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0510

AC:

541

AN:

10598

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0484

AC:

3288

AN:

67970

Other (OTH)

AF:

0.0294

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

242

484

725

967

1209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0412

Hom.:

248

Bravo

AF:

0.0292

ESP6500AA

AF:

0.00671

AC:

ESP6500EA

AF:

0.0329

AC:

264

ExAC

AF:

0.0159

AC:

1662

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 13, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16470590, 27884173, 29676077, 27116602, 23437219, 18586324, 20804470, 8755917) -

not specified

Benign:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary angioedema type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0065

T;T

Eigen

Benign

0.17

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.60

PhyloP100

0.25

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.032

ClinPred

0.012

GERP RS

-0.41

PromoterAI

0.20

Neutral

(source)

Mutation Taster

=294/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00053

dbscSNV1_RF

Benign

0.19

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over